Human Nasal and Lung Tissues Infected Ex Vivo with SARS-CoV-2 Provide Insights into Differential Tissue-Specific and Virus-Specific Innate Immune Responses in the Upper and Lower Respiratory Tract.

The nasal mucosa constitutes the primary entry site for respiratory viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While the imbalanced innate immune response of end-stage coronavirus disease 2019 (COVID-19) has been extensively studied, the earliest stages of SARS-CoV-2 infection at the mucosal entry site have remained unexplored. Here, we employed SARS-CoV-2 and influenza virus infection in native multi-cell-type human nasal turbinate and lung tissues ex vivo, coupled with genome-wide transcriptional analysis, to investigate viral susceptibility and early patterns of local mucosal innate immune response in the authentic milieu of the human respiratory tract. SARS-CoV-2 productively infected the nasal turbinate tissues, predominantly targeting respiratory epithelial cells, with a rapid increase in tissue-associated viral subgenomic mRNA and secretion of infectious viral progeny. Importantly, SARS-CoV-2 infection triggered robust antiviral and inflammatory innate immune responses in the nasal mucosa. The upregulation of interferon-stimulated genes, cytokines, and chemokines, related to interferon signaling and immune-cell activation pathways, was broader than that triggered by influenza virus infection. Conversely, lung tissues exhibited a restricted innate immune response to SARS-CoV-2, with a conspicuous lack of type I and III interferon upregulation, contrasting with their vigorous innate immune response to influenza virus. Our findings reveal differential tissue-specific innate immune responses in the upper and lower respiratory tracts that are specific to SARS-CoV-2. The studies shed light on the role of the nasal mucosa in active viral transmission and immune defense, implying a window of opportunity for early interventions, whereas the restricted innate immune response in early-SARS-CoV-2-infected lung tissues could underlie the unique uncontrolled late-phase lung damage of advanced COVID-19. IMPORTANCE In order to reduce the late-phase morbidity and mortality of COVID-19, there is a need to better understand and target the earliest stages of SARS-CoV-2 infection in the human respiratory tract. Here, we have studied the initial steps of SARS-CoV-2 infection and the consequent innate immune responses within the natural multicellular complexity of human nasal mucosal and lung tissues. Comparing the global innate response patterns of nasal and lung tissues infected in parallel with SARS-CoV-2 and influenza virus, we found distinct virus-host interactions in the upper and lower respiratory tract, which could determine the outcome and unique pathogenesis of SARS-CoV-2 infection. Studies in the nasal mucosal infection model can be employed to assess the impact of viral evolutionary changes and evaluate new therapeutic and preventive measures against SARS-CoV-2 and other human respiratory pathogens.

Human Nasal Turbinate Tissues in Organ Culture as a Model for Human Cytomegalovirus Infection at the Mucosal Entry Site.

The initial events of viral infection at the primary mucosal entry site following horizontal person-to-person transmission have remained ill defined. Our limited understanding is further underscored by the absence of animal models in the case of human-restricted viruses, such as human cytomegalovirus (HCMV), a leading cause of congenital infection and a major pathogen in immunocompromised individuals. Here, we established a novel ex vivo model of HCMV infection in native human nasal turbinate tissues. Nasal turbinate tissue viability and physiological functionality were preserved for at least 7 days in culture. We found that nasal mucosal tissues were susceptible to HCMV infection, with predominant infection of ciliated respiratory epithelial cells. A limited viral spread was demonstrated, involving mainly stromal and vascular endothelial cells within the tissue. Importantly, functional antiviral and proleukocyte chemotactic signaling pathways were significantly upregulated in the nasal mucosa in response to infection. Conversely, HCMV downregulated the expression of nasal epithelial cell-related genes. We further revealed tissue-specific innate immune response patterns to HCMV, comparing infected human nasal mucosal and placental tissues, representing the viral entry and the maternal-to-fetal transmission sites, respectively. Taken together, our studies provide insights into the earliest stages of HCMV infection. Studies in this model could help evaluate new interventions against the horizontal transmission of HCMV.IMPORTANCE HCMV is a ubiquitous human pathogen causing neurodevelopmental disabilities in congenitally infected children and severe disease in immunocompromised patients. The earliest stages of HCMV infection in the human host have remained elusive in the absence of a model for the viral entry site. Here, we describe the establishment and use of a novel nasal turbinate organ culture to study the initial steps of viral infection and the consequent innate immune responses within the natural complexity and the full cellular repertoire of human nasal mucosal tissues. This model can be applied to examine new antiviral interventions against the horizontal transmission of HCMV and potentially that of other viruses.

The Case for Whole-Person Integrative Care.

Rationale: There is a need for medicine to deliver more whole-person care. This is a narrative review of several models of whole-person care and studies that illustrate the business case for whole-person models in primary care. Objectives: To provide an overview of what whole-person care models exist and explore evidence to support these models. Study Selection: Representative whole-person care models widely used in the United States are summarized and evaluated. Selected studies focused on outpatient primary care with examples from programs that integrate the delivery of conventional medical care, complementary and alternative medicine, and self-care within the context of social and cultural environments. Methods: Pubmed search conducted December 2020-February 2021. Two iterative searches using terms for "Whole Health Veterans Administration," "integrative medicine," "integrative health," "complementary and alternative medicine," and, as they related to the outcomes, of "health outcomes," "cost-effectiveness," "cost reduction," "patient satisfaction," and "physician satisfaction." Additional studies were identified from an initial search and the authors' experience of over 50 years. We looked for studies of whole-person care used in general primary care, those not using a single modality and only from United States practices. Results: A total of 125 (out of 1746) studies were found and met our inclusion criteria. We found that whole-person models of primary care exist, are quite heterogeneous in their approaches, and routinely report substantial benefits for improving the patient experience, clinical outcomes and in reducing costs. Conclusions: Evidence for the benefit of whole-person care models exist but definitions are quite heterogenous and unfocused. There is a need for more standardization of whole-person models and more research using whole systems approaches rather than reductionistic attempts using isolated components.

Are Invasive Procedures Effective for Chronic Pain? A Systematic Review.

OBJECTIVE: To assess the evidence for the safety and efficacy of invasive procedures for reducing chronic pain and improving function and health-related quality of life compared with sham (placebo) procedures. DESIGN: Systematic review with meta-analysis. METHODS: Studies were identified by searching multiple electronic databases, examining reference lists, and communicating with experts. Randomized controlled trials comparing invasive procedures with identical but otherwise sham procedures for chronic pain conditions were selected. Three authors independently extracted and described study characteristics and assessed Cochrane risk of bias. Two subsets of data on back and knee pain, respectively, were pooled using random-effects meta-analysis. Overall quality of the literature was assessed through Grading of Recommendations, Assessment, Development, and Evaluation. RESULTS: Twenty-five trials (2,000 participants) were included in the review assessing the effect of invasive procedures over sham. Conditions included low back (N = 7 trials), arthritis (4), angina (4), abdominal pain (3), endometriosis (3), biliary colic (2), and migraine (2). Thirteen trials (52%) reported an adequate concealment of allocation. Fourteen studies (56%) reported on adverse events. Of these, the risk of any adverse event was significantly higher for invasive procedures (12%) than sham procedures (4%; risk difference = 0.05, 95% confidence interval [CI] = 0.01 to 0.09, P = 0.01, I2 = 65%). In the two meta-analysis subsets, the standardized mean difference for reduction of low back pain in seven studies (N = 445) was 0.18 (95% CI = -0.14 to 0.51, P = 0.26, I2 = 62%), and for knee pain in three studies (N = 496) it was 0.04 (95% CI = -0.11 to 0.19, P = 0.63, I2 = 36%). The relative contribution of within-group improvement in sham treatments accounted for 87% of the effect compared with active treatment across all conditions. CONCLUSIONS: There is little evidence for the specific efficacy beyond sham for invasive procedures in chronic pain. A moderate amount of evidence does not support the use of invasive procedures as compared with sham procedures for patients with chronic back or knee pain. Given their high cost and safety concerns, more rigorous studies are required before invasive procedures are routinely used for patients with chronic pain.

Measuring nonspecific factors in treatment: item banks that assess the healthcare experience and attitudes from the patient's perspective.

PURPOSE: Nonspecific factors that accompany healthcare treatments, such as patients' attitudes and expectations, are important parts of the experience of care and can influence outcomes. However, no precise, concise, and generalizable instruments to measure these factors exist. We report on the development and calibration of new item banks, titled the Healing Encounters and Attitudes Lists (HEAL), that assess nonspecific factors across a broad range of treatments and conditions. METHODS: The instrument development methodology of the Patient-Reported Outcomes Measurement Information System (PROMIS(®)) was used. Patient focus groups and clinician interviews informed our HEAL conceptual model. Literature searches of eight databases yielded over 500 instruments and resulted in an initial item pool of several thousand items. After qualitative item analysis, including cognitive interviewing, 296 items were included in field testing. The calibration sample included 1657 respondents, 1400 obtained through an Internet panel and 257 from conventional and integrative medicine clinics. Following exploratory and confirmatory factor analyses, the HEAL item banks were calibrated using item response theory. RESULTS: The final HEAL item banks were Patient-Provider Connection (57 items), Healthcare Environment (25 items), Treatment Expectancy (27 items), Positive Outlook (27 items), and Spirituality (26 items). Short forms were also developed from each item bank. A six-item short form, Attitudes toward Complementary and Alternative Medicine (CAM), was also created. CONCLUSIONS: HEAL item banks provided substantial information across a broad range of each construct. HEAL item banks showed initial evidence of predictive and concurrent validity, suggesting that they are suitable for measuring nonspecific factors in treatment.

Randomized effectiveness trial of a brief course of acupuncture for posttraumatic stress disorder.

BACKGROUND: Initial posttraumatic stress disorder (PTSD) care is often delayed and many with PTSD go untreated. Acupuncture appears to be a safe, potentially nonstigmatizing treatment that reduces symptoms of anxiety, depression, and chronic pain, but little is known about its effect on PTSD. METHODS: Fifty-five service members meeting research diagnostic criteria for PTSD were randomized to usual PTSD care (UPC) plus eight 60-minute sessions of acupuncture conducted twice weekly or to UPC alone. Outcomes were assessed at baseline and 4, 8, and 12 weeks postrandomization. The primary study outcomes were difference in PTSD symptom improvement on the PTSD Checklist (PCL) and the Clinician-administered PTSD Scale (CAPS) from baseline to 12-week follow-up between the 2 treatment groups. Secondary outcomes were depression, pain severity, and mental and physical health functioning. Mixed model regression and t test analyses were applied to the data. RESULTS: Mean improvement in PTSD severity was significantly greater among those receiving acupuncture than in those receiving UPC (PCLΔ=19.8±13.3 vs. 9.7±12.9, P<0.001; CAPSΔ=35.0±20.26 vs. 10.9±20.8, P<0.0001). Acupuncture was also associated with significantly greater improvements in depression, pain, and physical and mental health functioning. Pre-post effect-sizes for these outcomes were large and robust. CONCLUSIONS: Acupuncture was effective for reducing PTSD symptoms. Limitations included small sample size and inability to parse specific treatment mechanisms. Larger multisite trials with longer follow-up, comparisons to standard PTSD treatments, and assessments of treatment acceptability are needed. Acupuncture is a novel therapeutic option that may help to improve population reach of PTSD treatment.

The current state of the science for active self-care complementary and integrative medicine therapies in the management of chronic pain symptoms: lessons learned, directions for the future.

OBJECTIVES: Chronic pain management typically consists of prescription medications or provider-based, behavioral, or interventional procedures which are often ineffective, may be costly, and can be associated with undesirable side effects. Because chronic pain affects the whole person (body, mind, and spirit), patient-centered complementary and integrative medicine (CIM) therapies that acknowledge the patients' roles in their own healing processes have the potential to provide more efficient and comprehensive chronic pain management. Active self-care CIM (ACT-CIM) therapies allow for a more diverse, patient-centered treatment of complex symptoms, promote self-management, and are relatively safe and cost-effective. To date, there are no systematic reviews examining the full range of ACT-CIM used for chronic pain symptom management. METHODS: A systematic review was conducted, using Samueli Institute's rapid evidence assessment of the literature methodology, to rigorously assess both the quality of the research on ACT-CIM modalities and the evidence for their efficacy and effectiveness in treating chronic pain symptoms. A working group of subject matter experts was also convened to evaluate the overall literature pool and develop recommendations for the use and implementation of these modalities. RESULTS: Following key database searches, 146 randomized controlled trials were included in the review. CONCLUSION: This article summarizes the current state of the science, lessons learned from the gaps exposed by the review, as well as suggestions for next steps toward translation for the field. Although the review's entire scope is detailed throughout the current Pain Medicine supplement, the authors encourage the use of this report as a guide for future ACT-CIM research.

Implementing Whole Person Primary Care: Results from a Year-Long Learning Collaborative.

PURPOSE: The National Academies of Medicine report on Implementing High-Quality Primary Care calls for a transformation of the primary care to a "whole person" model that is person-centered, relationship-based and takes into account the social, spiritual, emotional and behavioral aspects of health. However, our current delivery tools, such as the SOAP Note, do not sufficiently capture and organize the delivery of these elements in practice. To explore how to remedy this, an Integrative Health Learning Collaborative (IHLC) was established to implement and test new tools for changing primary care practices toward whole person care. METHODS: The IHLC comprised primary care practices committed to changing to a whole person care model of care along with a panel of experts in integrative health and change management. The IHLC met virtually monthly. Representatives from each practice and an assigned expert met to strategize and adapt the tools to their environment and practice. The practices used previously developed tools (the HOPE Note toolkit), change management tools, and quality improvement techniques to introduce, implement, and evaluate the changes. RESULTS: Sixteen clinics completed the process after 1 year. Overall, practices used the HOPE Note tools in 942 patients. Participants reported changes on the effectiveness of the collaborative (1) on clinical practice, (2) on the skills and attitudes of participants; and (3) the support in change management. CONCLUSIONS: This online learning collaborative supported practices implementing a whole person care model in primary care and improved the understanding, skills, and delivery ability of whole person care in all clinics completing the program.

Complementary medicine for fatigue and cortisol variability in breast cancer survivors: a randomized controlled trial.

BACKGROUND: Fatigue is a chief complaint in cancer patients, and warrants effective treatment. Biofield therapies are complementary medicine approaches used by cancer populations. There is little information about their efficacy. METHODS: This blinded, randomized controlled trial examined the effects of 4 weeks (eight 1-hour sessions) of biofield healing compared with mock healing and a waitlist control group on fatigue in 76 fatigued breast cancer survivors (stages I-IIIa). Secondary outcomes were diurnal cortisol variability (via estimates of cortisol slope), depression, and quality of life (QOL). Treatment belief was assessed to explore whether belief predicted outcomes. Data were analyzed via hierarchical linear modeling. RESULTS: There were no significant differences between biofield healing and mock healing on belief; 75% thought they received biofield healing. Compared with controls, biofield healing significantly decreased total fatigue (P < .0005, Cohen's d = 1.04), as did mock healing (P = .02, Cohen's d = 0.68), with no significant differences between biofield healing and mock healing. Cortisol slope significantly decreased for biofield healing versus both mock healing and control (P < .04 in both cases; Cohen's d = 0.58). Belief predicted changes in QOL over and above group (P = .004, Cohen's d = 0.84). Belief did not impact fatigue or cortisol variability. CONCLUSIONS: Nonspecific factors are important in responses to biofield interventions for fatigue. Belief predicts QOL responses but not fatigue or cortisol variability. Biofield therapies increase cortisol variability independent of belief and other nonspecific factors. There is a need to further examine the effects of specific processes of biofield healing on outcomes for cancer populations.

Addressing the Long COVID Crisis: Integrative Health and Long COVID.

While COVID-19 has killed millions of people globally, its lasting effects on the health and well-being of entire populations are just becoming clear. As many as 30% of those diagnosed with COVID-19 report continuing health-related problems, regardless of the severity of the initial infection. Given the infection rate in the world, that translates to between 5.4 and 17.9 million globally; about 700 000 in the US. The syndrome goes by many names; here we call it "long COVID." Patients experience a wide range of symptoms, including serious organ system effects such as pulmonary fibrosis, myocarditis, new diabetes diagnoses, stroke, and other cerebrovascular events. They also experience ongoing pain, fatigue, and cognitive dysfunction. We suggest here that these patients require an integrative health approach, one that combines traditional medical management, non-pharmacological approaches, and behavior and lifestyle changes. Such an approach has been shown to be beneficial in other chronic illnesses such as fibromyalgia, chronic fatigue syndrome, and post-Lyme disease.

Breast Cancer Survivorship and Level of Institutional Involvement Utilizing Integrative Oncology.

OBJECTIVE: Integrative oncology is widely used by patients with breast cancer. This study aims to investigate the relationship between the survival outcomes of breast cancer patients and the level of involvement in integrative oncology at the institutions treating them. METHODS: Claims-based data were used to find 4,815 newly diagnosed breast cancer patients treated between January 2013 and December 2014 for survival analysis. A scoring system was developed by asking oncologists about their institutions' efforts to educate, support, and provide funding for 12 complementary and lifestyle approaches. Cohort analysis using two-tailed chi-square and a separate multivariate model using SMOTE and lasso regression were used. Nine variables across patient and institutional profiles were included. The model coefficients were exponentiated and presented as odds ratios. RESULTS: 173 patients mapped to 103 institutions and 103 oncologists. The median patient age was 51, and 8% were metastatic. Institutions were scored for integrative oncology involvement and placed into four cohorts. Low-scoring institutions showed less effort to educate, support, and provide integrative therapies compared to others. The 5-year survival of patients in the low cohort was directionally but not significantly lower than others. In the multivariate model, a composite integrative oncology score was shown to increase 5-year survival odds three times for institutions in the low-mid cohort and 48% in the mid-high, compared to the low. CONCLUSION: Crossing the threshold beyond 'low' involvement in integrative oncology represents a new path to incremental survival benefit for many cancer patients. Entities invested in the survival of breast cancer patients should increase education, access, and funding for a core set of six therapies: nutrition counselling, exercise counselling, patient support groups, spiritual services, meditation, and psycho-oncology support.

Methodological complexities associated with systematic review of healing relationships.

BACKGROUND/CONTEXT: There is growing recognition within the field of medicine that healing and healing relationships are important and that developing evidence-based medicine approaches to healing should be an important aspect of this emerging field, including the use of systematic reviews. Health care leaders charged with developing healing initiatives in hospitals often are frustrated in their attempts to find rigorous reviews of the literature to support their programs. OBJECTIVE: The objective of this project was to conduct a systematic review that asked, "What is the return on investment to hospitals that implement programs aimed at enhancing healing relationships?" METHODS: A comprehensive literature search using several electronic databases was conducted to locate studies that evaluated hospital-based programs involving "healing relationships." All studies found were evaluated as to their relevance to the study and screened for methodological quality. RESULTS: Research investigators found broad heterogeneity across the 80 included studies with regard to stated aims, target populations, outcomes measured, measurement tools employed, and evaluation methods used. Only 10 articles were categorized as being methodologically strong. CONCLUSIONS: Results of the systematic review highlighted challenges in synthesizing knowledge about healing that included absence of widely accepted definitions and language around "healing", locating literature published across many different disciplines, and absence of standards for conducting rigorous program evaluations in hospitals. A less formal qualitative review of included studies also revealed themes in the literature that provide clues about the professional, social, cultural, and historical influences that have helped to shape the evidence base to date.

Enzyme stabilization by glass-derived silicates in glass-exposed aqueous solutions.

OBJECTIVES: To analyze the solutes leaching from glass containers into aqueous solutions, and to show that these solutes have enzyme activity stabilizing effects in very dilute solutions. METHODS: Enzyme assays with acetylcholine esterase were used to analyze serially succussed and diluted (SSD) solutions prepared in glass and plastic containers. Aqueous SSD preparations starting with various solutes, or water alone, were prepared under several conditions, and tested for their solute content and their ability to affect enzyme stability in dilute solution. RESULTS: We confirm that water acts to dissolve constituents from glass vials, and show that the solutes derived from the glass have effects on enzymes in the resultant solutions. Enzyme assays demonstrated that enzyme stability in purified and deionized water was enhanced in SSD solutions that were prepared in glass containers, but not those prepared in plastic. The increased enzyme stability could be mimicked in a dose-dependent manner by the addition of silicates to the purified, deionized water that enzymes were dissolved in. Elemental analyses of SSD water preparations made in glass vials showed that boron, silicon, and sodium were present at micromolar concentrations. CONCLUSIONS: These results show that silicates and other solutes are present at micromolar levels in all glass-exposed solutions, whether pharmaceutical or homeopathic in nature. Even though silicates are known to have biological activity at higher concentrations, the silicate concentrations we measured in homeopathic preparations were too low to account for any purported in vivo efficacy, but could potentially influence in vitro biological assays reporting homeopathic effects.

A new model of care to return holism to family medicine.

Family medicine's leadership in primary care is slipping as it loses its vision of whole-person care. This model of care can help us better manage and combat chronic disease.

Greater Well-Being in More Physically Active Cancer Patients Who Are Enrolled in Supportive Care Services.

Background: Cancers are one of the leading causes of mortality worldwide. Cancer patients are increasingly seeking integrative care clinics to promote their health and well-being during and after treatment. Aim: To examine relationships between physical activity (PA) and quality of life (QoL) in a sample of cancer patients enrolling in integrative care in a supportive care clinic. Also, to explore circulating inflammatory biomarkers and heart rate variability (HRV) in relationship to PA and QoL. Methods: A cross-sectional design of adult patients who sought care in the InspireHealth clinic, Vancouver, British Columbia, Canada. Patients with complete PA data (n = 118) answered psychosocial questionnaires, provided blood samples, and received HRV recordings before enrollment. Patients were stratified into "less" versus "more" active groups according to PA guidelines (150 minutes of moderate or 75 minutes of vigorous PA or an equivalent combination). Results: Breast (33.1%) and prostate (10.2%) cancers were the most prevalent primary diagnoses. Patients engaging in more PA reported better physical (U = 1265.5, P = .013), functional (U = 1306.5, P = .024), and general QoL (U = 1341, P = .039), less fatigue (U = 1268, P = .014), fewer physical cancer-related symptoms (U = 2.338, P = .021), and less general distress (U = 2.061, P = .021). Between PA groups, type of primary cancer diagnosis differed (χ2 = 41.79, P = .014), while stages of cancer did not (χ2 = 3.95, P = .412). Fewer patients reported depressed mood within the more active group (χ2 = 6.131, P = .047). More active patients were also less likely to have ever used tobacco (χ2 = 7.41, P = .025) and used fewer nutritional supplements (χ2 = 39.74, P ≤ .001). An inflammatory biomarker index was negatively correlated with vigorous PA (rs = -0.215, P = .022). Multivariable linear regression (R2 = 0.71) revealed that age (ß = 0.22; P = .001), fatigue (ß = -0.43; P ≤ .001), anxiety (ß = -0.14; P = .048), and social support (ß = 0.38; P = .001) were significant correlates of QoL.